Atherosclerosis

Atherosclerosis
1. atheroma-focal disease of the intima-endothelial layer of large & medium sized arteries
2. risk factors
  1. family history of ischaemic heart disease
  2. modifable risk factors:raised/reduced LDL,hypertension,obesity,physical inactivity,smoking,diabetes mellitus...
3. stages
  1. 1.Endothelial dysfunction (altered PGI2 & NO biosynthesis)
  2. 2.Endothelium injury (eg from disturbed blood flow at vessel junctions) leads to monocyte attachment to endothelium
  3. 3.Attatched monocytes & ECs generate free radicals, oxidising LDL bound to ECs (lipid peroxidation)
  4. 4.Oxidised LDL is taken up by macrophages, which become foam cells. These migrate sub-endothelially to form fatty streaks (precursors of atheroma)
  5. 5. SMC hyperplasia (uncontrolled proliferation) & matrix deposition. This leads to a dense fibrous cap overlying a lipid-rich core
  6. 6. Rupture leading to a thrombus formation (MI/blood clots)
Lipoprotein Transport
1. lipid & cholesterol are transported in blood as lipoproteins, 4 main classes: chylomicrons, HDL (exogenous transport), LDL & VLDL (endogenous)
2. Transport of exogenous lipids
  1. -chylomicrons transport dietary lipids from the gut via lymph & plasma to capillary beds
  2. Core triglycerides are then hydrolysed to free fatty acids by lipoprotein (LP)-lipase
  3. Chylomicron remnants transport cholesterol esters to the liver where they are endocytosed
  4. Released cholesterol is either stored, oxidised to bile acids (secreted in bile) or transported with triglycerides by endogenous transport pathway
3. Transport of endogenous lipids
  1. Cholesterol & triglycerides transport from liver to the tissues by VLDL
  2. Triglycerides are taken up by the tissues, leading LDL containing cholesterol esters
  3. Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoprotein
  4. Cholesterol can return to plasma from tissues in HDL particles
LDL & thombosis
1. lipoprotein(A) in LDL contains lipids and Apo(A). Apo(A) inhibits plasmin formation, thereby inhibiting fibrinolysis & promoting thrombosis
2. LDL also activates platelets, further driving thrombosis
Dyslipidaemia
1. elevated LDL & reduced HDL cholesterol levels cause increased risk of cardiovascular diseases
  1. primary
    1. genetic & classified into 6 phenotypes
      1. eg. type IIa hyper-lipoproteinaemia (LDL receptor defects=increased LDL, dysfunctional thrombosis & increased risk of ischaemic heart disease
  2. Secondary
    1. environment, lifestyle- risk factor for diabetes, renal, thyroid & liver diseases
Lipid lowering drugs
1. 1. Statins
  1. eg Simvastatin, lovostatin, prevastatin
  2. Competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis-lower cholesterol syn=increased LDL receptor syn
    1. =increased LDL clearance. MAIN EFFECT IS TO REDUCE LDL-CHOLESTEROL CONCS
  3. Also:improved endothelial function, reduced vascular inflammation, reduced platelet aggregation, increased neovascularization under hypoxia
    1. increased circulating endothelial cell progenitors, plaque stabilisation, reduced atherosclerosis & plaque stabilisation, increased fibrinolysis
  4. Clinical uses-reduce risk of MI & stroke in patients with symptomatic atherosclerosis disease
    1. prevention of arterial disease in patients with high risks
      1. Atorvastatin has long-lasting effects & is used to lower serum cholesterol levels in patients with LDL-R mutations
  5. first line of treatment
2. 2. Fibrates
  1. agonists of nuclear receptor PPARa (activation stimulates lipoprotein lipase production)=increased triglyceride hydrolysis in chlymicrons & VLDL
  2. Plasma triglyceride levels are reduced & FFA are released for storage in fat or for metabolic use in striated muscle
    1. reduce SMC inflammation by inhibiting txn factor NF-kB levels (reduces plasma fibrinogen)
      1. eg. Bezafibrate, ciprofibrate, gemfibrozil, fenofibrate, clofibrate
3. 3. Bile acid resins
  1. anion exhchange resins (colestyramine, colestipol)-sequester bile acids in intestine & prevent their reabsorbtion & recirculation
    1. =decreased absorption of exogenous cholesterol & increased metabolism of endogenous cholesterol into bile acids in liver
      1. =LDL receptor expression on liver increased=further removal of LDL from blood=13% fall in cholesterol levels,20-25% reduction coronary artery disease
        side effects- nausea, bloating & diarrhoea

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Atherosclerosis

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